Current Molecular Imaging (v.1, #1)

Editorial by Sandip Basu, Rakesh Kumar, Abass Alavi (1-2).

Cancer is uncontrolled growth of an abnormal mass of cells. Cancerous cells exhibit differential expression of receptors, as compared to healthy cells, which can be employed to deliver imaging and/or therapeutic agents specifically to the tumor tissue. Specific targeting of proteins on cancer cells for molecular imaging by nanoparticles loaded with multiple reporters can enhance the sensitivity of cancer detection over non-targeted small molecule agents. Nanoparticles (NPs) are one of the major technologies that utilize receptor overexpression to image and manipulate cancer cells. A plethora of NPs such as liposomes, polymeric, gold, iron oxide NPs and dendrimers have been investigated for cancer imaging and therapy. However, this mini-review is focused on liposomes, polymeric NPs and dendrimers, modified with receptor- targeting peptides. Conjugation of receptor-targeting ligands onto nanocarriers enables specific delivery to tumor tissue. PEGylation of nanocarriers further improves their bioavailability and pharmacokinetic properties. Peptide-based receptor-targeted nano-vectors present a promising future for clinical treatment and diagnosis of cancer. Peptidefunctionalized nanocarriers can be designed readily and synthesized with ease. This mini-review aims to provide an overview of recent developments in peptide-based receptor-targeted nanoparticles in cancer imaging and therapy.

Strategies for Target-Specific Contrast Agents for Magnetic Resonance Imaging by Sashiprabha Vithanarachchi, Matthew Allen (12-25).
This review describes recent research efforts focused on increasing the specificity of contrast agents for proton magnetic resonance imaging (MRI). Contrast agents play an indispensable role in MRI by enhancing the inherent contrast of images; however, the non-specific nature of current clinical contrast agents limits their usefulness. This limitation can be addressed by conjugating contrast agents or contrast-agent-loaded carriers—including polymers, nanoparticles, dendrimers, and liposomes—to molecules that bind to biological sites of interest. An alternative approach to conjugation is synthetically mimicking biological structures with metal complexes that are also contrast agents. In this review, we describe the advantages and limitations of these two targeting strategies with respect to translation from in vitro to in vivo imaging while focusing on advances from the last ten years.

Early diagnosis remains the best method of improving the odds of curing breast cancer. Mammography is an effective imaging tool in diagnosis of breast cancer. However, false negatives occur frequently, particularly when imaging post-surgical recurrence, fibrocystic breast disease and dense breast tissue in younger women. Other imaging modalities such as ultrasonography, magnetic resonance imaging and computed tomography initiated to increase the diagnostic accuracy of mammography, have strengths and weaknesses in terms of sensitivity, specificity, spatial and temporal resolution, contrast and cost. The application of nuclear medicine techniques to study patients with breast cancer has recently raised its profile, particularly in the investigation of indeterminate mammographic lesions and for overcoming limitations of other imaging techniques. For increasing sensitivity and specificity of nuclear medicine techniques, researchers are studying on targeted molecular imaging methods. The recent advances in molecular and cellular biology have facilitated the discovery of novel molecular targets of breast tumor cells such as key molecules involved in proliferation, differentiation, cell death and apoptosis, angiogenesis and metastasis. In this paper, the history of radioimmunodetection of breast cancer as a targeting molcular imaging method will be reviewed.

Beta cell mass is dynamic, and changes during neonatal growth and development, during pregnancy, and in response to chronic metabolic stress, such as obesity and diabetes. Molecular imaging techniques can be used to provide real-time readouts on subclinical changes in beta cell mass, and, in the process, enhance our understanding of the molecular processes that govern its regulation. The strategy of engineering beta cells to express endogenous contrast for imaging by fluorescence, bioluminescence and positron emission tomography (PET) has been especially useful in developing novel insights into the timing of the decline in functional beta cell mass during the progression of diabetes. There have also been some recent exciting developments in the use of MRI in detecting beta cell function by tagging the movement of cations across the cell membrane in response to glucose. While such imaging strategies may not be immediately translated to the clinic, they have provided the opportunity to directly visualize the islet development and formation as well as the subclinical declines in beta cell mass that precede the onset of overt diabetes. This review will discuss the impact of transgenic mouse models and MR imaging of cation flux on the field of beta cell imaging.

Molecular imaging of apoptosis can be applied for diagnosis and/or therapeutics in the field of oncology since it may allow rapid assessment of cancer treatment. Various imaging techniques are employed to visualize apoptotic cells in vivo to probe function of enzymatic and morphologic events occurring during cell death. In the present review, we outline recent investigation of imaging molecules targeting early apoptotic processes, such as externalization of phosphatidylserine, activation of caspases, and other apoptotic changes which can be de novo targets on the cell surface or inside of the cells. Including Annexin-A5 derivatives, which are the most successful and widely applied approaches in apoptosis imaging based on specific interaction with phophatidylserine, current researches of other phosphatidylserine indicators, caspase substrates/inhibitors, and numerous de novo imaging molecules are discussed with points of potential advantages and drawbacks. Two of them, 99mTc- or 123I-labeled annexin A5 and 18F-ML10, have progressed to clinical trials which hold great promise for specific imaging of apoptosis in several types of cancer patients for early assessment of therapy. Furthermore, new targets and accompanying new tracers such as histone H1 and ApoPep-1, respectively, and development of translatable labeling platforms will lead to a rapid expansion of apoptosis imaging allowing fast assessment of therapy efficacy in cancer.

Accurate, robust and reproducible segmentation of positron emission tomography (PET) images is very important both in terms of radiotherapy planning as well as treatment assessment. However, due to high noise and poor resolution of PET scanner, it still remains a daunting task. Threshold based segmentation methods are proved to be robust to noise and resolution compared to other segmentation methods (e.g. clustering, gradient based etc.). Numerous publications deal with the topic. This paper reviews different fixed and adaptive threshold methods proposed in literature in a common mathematical framework. The paper also highlights the purpose of segmentation of PET images from two perspectives – radiotherapy planning and treatment response. A few recommendations are suggested at the end.

New Ultrafast Cardiac SPECT Cameras (UCS) by Miguel Gorenberg (69-74).
Myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) has widespread clinical use because of its well-documented diagnostic accuracy for detecting coronary artery disease (CAD). <p/> <p> Cardiac SPECT imaging needs to become shorter and use lower radiation doses in order to compete with other available noninvasive imaging modalities. Recently introduced cadmium zinc telluride (CZT) SPECT cameras have the potential to achieve both of these goals. New SPECT CZT camera technology drastically reduces imaging time for patients while also reducing their radiation exposure compared to previously used technologies, without any loss of image quality. <p/> <p> This article describes these innovations, which provide a strong foundation for the continued success of myocardial perfusion SPECT.

C. elegans is a useful model for studying neuronal and genetic mechanisms underlying behavior. Calcium imaging, facilitated by genetically encoded calcium indicators, is a convenient tool for linking the function of a gene, neuron, circuit and tissue with a particular behavioral phenotype. Because C. elegans has a transparent body, calcium imaging can be performed non-invasively in intact animals. Over 10 homemade calcium imaging systems have been used to study C. elegans, each with a unique strategy to achieve reliable and sensitive results. This review summarizes these strategies, and compare and contrast their underlying principles. This discussion may help the development of calcium imaging systems as better research tools.

The default mode network (DMN) is assumed as a set of brain regions that show increased activity during the resting-state condition and suppressed activity during the demanding task condition. Accumulating evidence from functional imaging studies such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) has revealed that alterations in DMN is present in aging, many psychiatric and neurological disorders. In Alzheimer's disease (AD), for example, the distribution of Aβ-amyloid protein (Aβ) deposition in the brain is considerably overlapped over the DMN. It is now considered that this Aβ accumulation is not only specific to the AD brain but to some cognitively normal elderly people. The Aβ accumulation seen in the DMN may be an ominous sign in the seemingly normal persons because these subjects with high Aβdeposition are very likely to develop AD in the future. Our recent study on the cognitive and physiological implications of Aβ accumulation to the DMN function in normal elderly people using PET has shown that the amount of Aβ deposits is negatively correlated with the DMN function, and the lower function of DMN is associated with poorer working memory performance. As expected, Aβ deposition in the brain, however minute the degree of its accumulation can be,may cause neuronal dis coordination in the DMN along with poor working memory in normal aging. Although articles on fMRI-based DMN activity are profuse, there are few papers on molecular imagingbased study on the DMN. In this paper, alterations in metabolism and neuro chemical responses in the DMN in aging and brain disorders are reviewed.

“Click Chemistry”for Molecular Imaging by Mengjing Wang, Yue Yuan, Gaolin Liang (87-95).
Click chemistry is a highly-selective and high-yield chemical approach which uses a wide scope of materials and does not call for purification. Molecular imaging is an in vivo characterization and measurement of biologic processes at the cellular and molecular level. Representative imaging modalities of molecular imaging are optical imaging, nuclear imaging, and magnetic resonance imaging (MRI). Up to date, click chemistry has been widely employed by molecular imaging to trap imaging probes on site and trace the biological events with high efficiency and high sensitivity. It has played an important role in early detection of disease, real-time monitoring of drug delivery and investigating the functions of biomolecules in vivo. Herein, we introduce the concept of click chemistry and illustrate the design of probes for molecular imaging based on the strategies of click chemistry.

ACKNOWLEDGEMENT by Bentham Science Publishers (96-96).